Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) amplification is a molecular driver for a subset of colorectal cancers (CRCs) and one of the major causes of anti-epidermal growth factor receptor (EGFR) treatment failure. Compared to dual anti-HER2 treatments, which have been shown to be effective in HER2-positive metastatic CRC patients, single-agent anti-HER2 therapy is rarely used to treat CRC. CASE SUMMARY: Herein, we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA (ctDNA) testing by next-generation sequencing following the failure of two lines of therapy. Subsequently, the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo. Moreover, serial ctDNA detection was used to monitor the efficacy of lapatinib. The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response. However, a high level of HER2 amplification was detected again at the time of disease progression. Finally, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression, which may explain the acquired resistance to lapatinib. CONCLUSION: This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy. It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.

Lung cancer treatment disparities in China: a question in need of an answer.

BACKGROUND: Substantial progress has been made in the treatment of malignancies in the People's Republic of China in recent years. The goal of this study was to identify the extent to which national treatment guidelines are being used to customize patient care in lung cancer and to analyze the reasons for treatment disparities. METHODS: Patient characteristics and treatments were investigated retrospectively for the period from October 2004 to January 2013 using the outpatient database of the Guangdong Lung Cancer Institute (GLCI) in China. RESULTS: A total of 2,535 outpatients with lung cancer were studied in this retrospective analysis. The treatment disparity was 45.3%. Overall, 20.6% of patients with stage I non-small cell lung cancer (NSCLC) were overtreated, and 20.1% of stage II patients were undertreated. Only 19.6% of stage IIIA patients and 30.7% of stage IIIB patients underwent the recommended combination of chemotherapy and radiotherapy, respectively. For advanced NSCLC, the greatest treatment disparity appeared in the second-line setting and beyond. Patients who were positive for epidermal growth factor receptor (EGFR) and receiving EGFR tyrosine kinase inhibitors experienced significant prolongation of survival compared with patients who were EGFR negative or whose EGFR mutation status was unknown (hazard ratio: 0.79; p = .037). The treatment disparities were significantly larger among patients aged younger than 65 years and in patients from developing regions compared with patients aged 65 years and older and from developed regions, respectively (p < .001, p = .046). The difference in treatment disparity was statistically significant between GLCI and other hospitals (p < .001). CONCLUSION: This retrospective study of a large number of patients from an outpatient oncology database demonstrated large disparities in the treatment of lung cancer in China. It is important to develop a new guideline for recommendations that are based on resource classification.

Prognostic significance of genotype and number of metastatic sites in advanced non-small-cell lung cancer.

BACKGROUND: TNM stage remains the most important prognostic factor in clinical practice. The 7th edition lung cancer staging system has not considered some important prognostic factors, such as the number of metastatic organ sites and the molecular biologic characterization. PATIENTS AND METHODS: Using driver gene alternation and tumor burden, advanced NSCLC cases were divided into 3 groups: M1-I group, epidermal growth factor (EGFR)-positive and/or anaplastic lymphoma kinase (ALK)-positive; MI-II, wild-type EGFR and ALK with intrathoracic metastasis or 1 distant metastatic organ with ≤ 3 metastasis lesions; and MI-III, wild-type EGFR and ALK with 1 distant metastatic organ with > 3 metastasis lesions or multiple metastatic organs. Overall survival was comparable between the 7th edition staging system and our category of M descriptors. RESULTS: A total of 627 patients with stage IV NSCLC newly diagnosed at Guangdong Lung Cancer Institute between January 2009 and July 2012 were enrolled in the present study. The median overall survival (OS) was 22.2 (95% CI, 19.590-24.810), 15.5 (95% CI, 13.176-17.824), and 10.0 (95% CI, 8.033-11.967) months for M1-I, M1-II, and M1-III, respectively (P < .001). According to the 7th edition of the TNM staging system, the median OS of the M1a and M1b groups was 22.8 (95% CI, 19.484-26.116) and 13.7 (95% CI, 11.793-15.607) months, respectively (P < .001). The maximum of the absolute values of the M1 category for our study and the 7th TNM staging system was 5.881 and 5.089, respectively. CONCLUSION: Advanced NSCLC could potentially be further divided into 3 subgroups according to the genotype and number of metastatic organ sites and metastasis lesions.

KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy.

BACKGROUND: The prognostic and predictive value of KRAS mutations in patients with lung cancer is controversial. Biases in disease stage, treatment regimen, small-scale patient studies, and biomarker status have led to inconsistent results in previous reports. METHODS: The KRAS and EGFR genes were examined in 1935 consecutive patients with non-small cell lung cancer. All patients were divided into KRAS mutation (KRAS group), EGFR mutation (EGFR group), and KRAS/EGFR wild type (WT group) groups. Randomly selected cases were paired with patients with the KRAS mutation, the EGFR mutation, and KRAS/EGFR wild type patients according to tumor, node, metastasis stage, time of first visit within 1 year, and pathology. Progression-free survival (PFS) and overall survival were evaluated by Kaplan-Meier and Cox models. RESULTS: The KRAS mutation rate for lung adenocarcinoma was 5.90 %. The overall survival was 14.47, 20.57, and 42.73 months for the KRAS group, WT group, and EGFR group, respectively (P < 0.001). Multivariate analysis indicated that KRAS mutation status was an independent prognostic factor (hazard ratio 2.69, 95 % confidence interval 1.91-3.80, P < 0.001). No difference was found in PFS and tumor responsiveness between patients with a KRAS mutation and those with wild type KRAS/EGFR for chemotherapy and EGFR tyrosine kinase inhibitors (TKI). PFS did not significantly differ for chemotherapy among the three groups (P = 0.270). CONCLUSIONS: KRAS mutation is a poor prognosis factor, but it is not an independent predictor of response to EGFR-TKI or chemotherapy in patients with lung cancer.

Identification of enriched driver gene alterations in subgroups of non-small cell lung cancer patients based on histology and smoking status.

BACKGROUND: Appropriate patient selection is needed for targeted therapies that are efficacious only in patients with specific genetic alterations. We aimed to define subgroups of patients with candidate driver genes in patients with non-small cell lung cancer. METHODS: Patients with primary lung cancer who underwent clinical genetic tests at Guangdong General Hospital were enrolled. Driver genes were detected by sequencing, high-resolution melt analysis, qPCR, or multiple PCR and RACE methods. RESULTS: 524 patients were enrolled in this study, and the differences in driver gene alterations among subgroups were analyzed based on histology and smoking status. In a subgroup of non-smokers with adenocarcinoma, EGFR was the most frequently altered gene, with a mutation rate of 49.8%, followed by EML4-ALK (9.3%), PTEN (9.1%), PIK3CA (5.2%), c-Met (4.8%), KRAS (4.5%), STK11 (2.7%), and BRAF (1.9%). The three most frequently altered genes in a subgroup of smokers with adenocarcinoma were EGFR (22.0%), STK11 (19.0%), and KRAS (12.0%). We only found EGFR (8.0%), c-Met (2.8%), and PIK3CA (2.6%) alterations in the non-smoker with squamous cell carcinoma (SCC) subgroup. PTEN (16.1%), STK11 (8.3%), and PIK3CA (7.2%) were the three most frequently enriched genes in smokers with SCC. DDR2 and FGFR2 only presented in smokers with SCC (4.4% and 2.2%, respectively). Among these four subgroups, the differences in EGFR, KRAS, and PTEN mutations were statistically significant. CONCLUSION: The distinct features of driver gene alterations in different subgroups based on histology and smoking status were helpful in defining patients for future clinical trials that target these genes. This study also suggests that we may consider patients with infrequent alterations of driver genes as having rare or orphan diseases that should be managed with special molecularly targeted therapies.